Mike: Hello, I'm Mike Clarke, podcast editor for the Cochrane Library. Many patients with moderate or severe chronic kidney disease will develop anaemia and a variety of treatments are available. In February 2023, the Cochrane Review of studies testing a range of erythropoietin drugs was updated and we asked first author, Edmund Chung from The Children's Hospital at Westmead in Australia to tell us about the latest findings in this podcast.

Edmund: Anaemia is a common complication of moderate-to-severe chronic kidney disease caused by reduced production of erythropoietin or EPO by the kidneys. It's associated with symptoms such as fatigue and breathlessness. Erythropoiesis-stimulating agents, or ESAs for short, are medications made of recombinant EPO and its synthetic derivatives, which have revolutionised the treatment of anaemia in chronic kidney disease. However, there are also some safety concerns with these agents because they can increase the risk of death and vascular events, such as stroke and myocardial infarction. These findings emerged in the early trials and were confirmed in the first Cochrane review of ESAs, published in 2006.
In 2014, we revised that review to summarise the evidence on the several formulations of ESA and to assess their relative efficacy and safety against each other. We did this in a network meta-analysis, to make best use of the totality of evidence to compare ESAs against each other and placebo. We identified 56 studies involving more than 15,000 participants but methodological limitations in over half the studies lowered our confidence in the findings. All ESAs except biosimilar ESAs prevented blood transfusions but there were no differences between ESAs. The comparative effects of all ESAs against each other or placebo on death, vascular events, and symptoms such as fatigue and breathlessness were uncertain.
Since the publication of that review, there have been many new studies assessing newer synthetic forms of ESAs, such as methoxy polyethylene glycol-epoetin beta and biosimilar ESAs and, so, we updated the review to bring in that evidence.
For this update, we found an additional 62 studies involving more than 9000 participants that were available up to April 2022 and the review now includes 117 studies with over 25000 participants. However, significant methodological limitations in most studies continue to reduce confidence in our findings and, overall, the results remain similar to 2014. It's also important to note that despite the large number of studies and participants in the review, the effect of ESAs was only observed for around seven months, which may be insufficient to detect differences in key outcomes, as death and vascular events.
Turning to the latest results, the network meta-analyses found that all ESAs had similar effects on preventing the need for blood transfusions compared to placebo, although the effects of methoxy polyethylene glycol-epoetin beta and biosimilar ESAs were not significant. The effect of ESAs compared with each other or with placebo on fatigue and breathlessness also remain inconclusive, due to a lack of data.
In terms of safety, there were no differences between any ESA compared with placebo or each other for death, vascular events, clotting of vascular access for dialysis, or kidney failure. All ESAs had a similar effect on raising blood pressure compared with placebo but the effects for biosimilar ESAs were not significant.
In summary, our review found no significant differences between ESAs for preventing blood transfusions or in their safety profile when used for treating anaemia in chronic kidney disease. We are unsure whether different ESAs are better at improving symptoms of anaemia, such as fatigue or breathlessness, which were not reported in most studies. Therefore, at present, the choice between ESA formulations is likely to be informed by cost, availability, and patient preferences such as treatment frequency.
As in 2014, this updated review calls again for larger and longer-term studies evaluating the effects of ESAs on patient-centred outcomes. These studies should use core outcome measures, as developed by the Standardised Outcomes in Nephrology, or SONG, initiative that reflect the priorities of patients, caregivers, clinicians, researchers, and policymakers. Finally, because ESAs are given either subcutaneously or intravenously, the emergence of hypoxia-inducible factor stabilisers as an oral treatment is attractive and studies evaluating these treatments should be included in future reviews.

Mike: To read the current update of this review, and watch for future updates, you can find it online at Cochrane Library dot com with a search for 'ESA and kidney disease'.